Abstract 834: Formation of DNA double-strand breaks in colon tumors after targeted alpha therapy with 211At-mAb

Abstract

Abstract Introduction: Targeted alpha therapy has shown promising results in preclinical and clinical studies. Alpha particle irradiation gives a high fraction of DNA double-strand breaks (DSB), as shown in vitro, resulting in a high probability of cell death. We have previously examined the therapeutic effects of 211At on solid colon carcinoma tumors (diameter approximately 1 cm), with tolerable activities (5 MBq/animals) resulting in non-palpable tumors within one week p.i. The aim of the present study was to investigate the formation of DNA DSB during tumor regression after radioimmunotherapy with 211At-mAb in a syngeneic rat colon carcinoma model. Methods: 18 rats bearing solid colon tumors (1 cm in diameter) between peritoneum and the abdominal muscle were injected intravenously with 5 MBq/animal 211At-BR96. Tumors were excised and paraffin-embedded after 10 min, 2 h, 8 h, 18 h, 24 h, and 48 h p.i. (3 tumors per time point). 53BP1 was stained by immunohistochemistry and used as a marker for DNA DSB. Untreated tumors were used as controls (n=9). DNA DSB were counted in central and peripheral tumor areas selected at random. Results: A few DNA DSB were detected in untreated tumors. Already 10 min p.i., the number of DNA DSB had increased slightly in peripheral tumor tissue. The number peaked 8 h p.i., when the number of DNA DSB had increased 50 times in the tumor periphery and 24 times in the tumor center. The number of DNA DSB then declined, but the difference between center and periphery remained, as expected considering the intratumoral distribution of radioimmunoconjugate. This correlates with the 211At half-life of 7.2 h. Conclusion: DNA DSB are formed early after injection of 211At-mAb and follows the intratumoral distribution of mAbs. Citation Format: Sophie E. Eriksson, Erika Elgström, Sture Lindegren, Tom Bäck. Formation of DNA double-strand breaks in colon tumors after targeted alpha therapy with 211At-mAb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 834. doi:10.1158/1538-7445.AM2017-834